Adenosine receptors co-operate with NMDA preconditioning to protect cerebellar granule cells against glutamate neurotoxicity.

N-Methyl-D-aspartate (NMDA) preconditioning is evoked by subtoxic concentrations of NMDA (50 microM), which has been shown previously to lead to transient resistance to subsequent lethal dose of glutamate or NMDA in cultured neurons. The purpose of this study was to investigate the participation of adenosine A1 and A2A receptors on NMDA preconditioning against glutamate-induced cellular damage in cerebellar granule cells. NMDA preconditioning prevented the stimulatory effect induced by glutamate on AMP hydrolysis, but not on ADP hydrolysis. The neuroprotection evoked by NMDA preconditioning against glutamate-induced cellular damage was prevented by the presence of adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT, 100 nM), but not by the adenosine A2A receptors antagonist, (4-(2[7-amino-2-(2-furyl {1,2,4}-triazolo{2,3-a{1,3,5}triazian-5-yl-aminoethyl)phenol (ZM 241385, 50 nM). Interestingly, a long-term treatment with CPT or ZM 241385 alone protected cells against glutamate-induced neurotoxicity. Moreover, the functionality of adenosine A1 receptor was not affected by NMDA preconditioning, but this treatment promoted adenosine A2A receptor desensitization, measured by cAMP accumulation. Taken together, the results described herein suggest that the neuroprotection evoked by NMDA preconditioning against cellular damage elicited by glutamate occurs through mechanisms involving adenosine A2A receptors desensitization co-operating with adenosine A1 receptors activation in cerebellar granule cells.